Faculty Bibliography

Homeostatic scaling of synaptic strengths is essential for maintenance of network "gain", but also poses a risk of losing the distinctions among relative synaptic weights, which are possibly cellular correlates of memory storage. Multiplicative scaling of all synapses has been proposed as a mechanism that would preserve the relative weights among them, because they would all be proportionately adjusted. It is crucial for this hypothesis that all synapses be affected identically, but whether or not this actually occurs is difficult to determine directly. Mathematical tests for multiplicative synaptic scaling are presently carried out on distributions of miniature synaptic current amplitudes, but the accuracy of the test procedure has not been fully validated. We now show that the existence of an amplitude threshold for empirical detection of miniature synaptic currents limits the use of the most common method for detecting multiplicative changes. Our new method circumvents the problem by discarding the potentially distorting subthreshold values after computational scaling. This new method should be useful in assessing the underlying neurophysiological nature of a homeostatic synaptic scaling transformation, and therefore in evaluating its functional significance.

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance

Background: Neurotrophin signaling of cholinergic basal forebrain (CBF) neurons is critical for survival and plasticity. Microaspiration of identified CBF neurons from postmortem human brain revealed a shift in balance of neurotrophin receptors toward cell death pathways during the progression of Alzheimer's disease (AD). Methods: In this study transcriptomic data from mouse basal forebrain cholinergic neurons (BFCNs; NCBI GEO GSE13379) were used to derive parameters for a deterministic kinetic model of the nerve growth factor (NGF) signaling pathway from Reactome, with TrkB receptor mechanisms added. This method is called Transcriptome-To-Reactome (TTR)-. The biosimulation was performed using COPASI software and included 11 compartments 435 species, and 263 reactions; 245 genes were used to determine initial values of species and kinetic values of reactions. The mouse BFCN model was considered baseline and a biosimulation was run with two doses of NGF, 500 m M and 10 mM, delivered as a bolus and for a 10 and 240 second duration, respectively. This approach tested selectively for p75 NTR and TrkA receptor mediated mechanisms. A second biosimulation test used a combination of 25 mM brain derived neurotrophic factor (BDNF) and 10 m M NGF as a continuous exposure for 60 min duration; this approach evaluated stimulation of p75 NTR TrkA, and TrkB. Based on the human microarray results demonstrating downregulation of TrkA (50%) and TrkB (60%), the corresponding parameters in the TTR biosimulation were decreased by the same amount. Results: Baseline results were validated from published literature on neuronal calcium levels mediated via the phospholipase C-g and inositol- 3-phosphate pathway at both bolus doses of NGF alone. With the corresponding parameters decreased in the TTR biosimulation, Figure 1: A) The reaction flux for c-RAF1 phosphorylation of MEK1 was delayed to peak value by 1.5 min from exposure, but the peak value was increased to 5 times the baseline value; B) Moreover, a slight shift t!

We report the elusive X-ray structure of the Dess-Martin periodinane (DMP), a hypervalent iodine reagent popular amongst synthetic chemists. In the solid state, the highly crystalline compound forms an intricate coordination polymer held together by intermolecular halogen and hydrogen bonds.

Background: Immunotherapy targeting hyperphosphorylated tau is a promising prospect to mitigate the neurodegenerative effects of tauopathies. Assessing the effectiveness of such immunotherapies often involves sacrifice of the animal. However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Methods: Twenty-five homozygous JNPL3 tangle transgenic mice underwent MEMRI at 6 months of age. Thirteen of the mice received tau immunotherapy with Tau379-408[P-Ser396,404] in alum adjuvant from 3 months of age, and twelve controls received an adjuvant alone. Imaging studies were performed on a 7-T micro-MRI. Mice were imaged pre-injection, then injected in one nostril with a solution of 2.5 M MnCl 2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36 and 48 hours, and finally at 7 days (Fig 1). The datasets were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model using MATLAB. Fitting enabled the estimation of the timing (Pt) and intensity (Pv) of the bolus peak of Mn, and maximal slope of uptake (Sv). Results: A significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer (35%, P <.005) and glomerular layer (36%, P <0.02) in treated JNPL3 mice compared to identical controls. There was also a significant increase in bolus peak value, Pv, in the mitral layer in the treated group (7%, P = 0.02). Furthermore, in the immunized mice, there was a strong trend for a decrease in the time to peak value, Pt (-9%P = 0.10), in the mitral cell layer, compared to the controls. Conclusions: Utilizing MEMRI's non-invasive, longitudinal measurements from 1 hour to 7 days, allowed us to detect substantial improvements in neuronal transport following tau immunotherapy. We are analyzing tau pathology in olfactory sections from these mice to assess the correlation of these benefits with clearance of tau lesions, which we have shown previously to occur with this treatment

Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10-11 months old), human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old), intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.

BACKGROUND: Mutations in any of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) can lead to an inherited chronic-progressive fatal brain disease of unknown aetiology termed leucoencephalopathy with vanishing white matter (VWM). VWM is one of the most prevalent childhood white matter disorders, which markedly deteriorates after inflammation or exposure to other stressors. eIF2B is a major housekeeping complex that governs the rate of global protein synthesis under normal and stress conditions. A previous study demonstrated that Eif2b5(R132H/R132H) mice suffer delayed white matter development and fail to recover from cuprizone-induced demyelination, although eIF2B enzymatic activity in the mutant brain is reduced by merely 20%. PRINCIPAL FINDINGS: Poor astrogliosis was observed in Eif2b5(R132H/R132H) mice brain in response to systemic stress induced by peripheral injections of lipopolysaccharide (LPS). Even with normal rates of protein synthesis under normal conditions, primary astrocytes and microglia isolated from mutant brains fail to adequately synthesise and secrete cytokines in response to LPS treatment despite proper induction of cytokine mRNAs. CONCLUSIONS: The mild reduction in eIF2B activity prevents the appropriate increase in translation rates upon exposure to the inflammatory stressor LPS. The data underscore the importance of fully-functional translation machinery for efficient cerebral inflammatory response upon insults. It highlights the magnitude of proficient translation rates in restoration of brain homeostasis via microglia-astrocyte crosstalk. This study is the first to suggest the involvement of microglia in the pathology of VWM disease. Importantly, it rationalises the deterioration of clinical symptoms upon exposure of VWM patients to physiological stressors and provides possible explanation for their high phenotypic variability.